Keep Cancer on the Run EUROPEAN INSTITUTE of ONCOLOGY, MILAN, ITALY Must Be Involved in the Growth-Sup- PETER CARMELIET Pressive Effects of Sts

HIGHLIGHTS

HIGHLIGHT ADVISORS ANTON BERNS TUMOUR SUPPRESSORS NETHERLANDS CANCER INSTITUTE, AMSTERDAM, THE NETHERLANDS PETER BOYLE Keep cancer on the run EUROPEAN INSTITUTE OF ONCOLOGY, MILAN, ITALY must be involved in the growth-sup- PETER CARMELIET pressive effects of STs. Further exam- CATHOLIC UNIVERSITY LEUVEN, ination of ST-treated cancer cells LEUVEN, BELGIUM revealed that the antiproliferative RON DEPINHO actions were not mediated by the HARVARD MEDICAL SCHOOL, conventional downstream cGMP BOSTON, MA, USA signalling pathway (which involves STEPHEN W. FESIK protein kinase G and phosphodi- ABBOTT LABORATORIES, esterase-3). But how does cGMP ABBOTT PARK, IL, USA production prevent proliferation of ELI GILBOA colon cancer cells? DUKE UNIVERSITY MEDICAL cGMP has also been shown to CENTER, DURHAM, NC, USA activate cyclic nucleotide gated TOMAS LINDAHL (CNG) channels. Pitari et al. found IMPERIAL CANCER RESEARCH that STs activate these channels in FUND, HERTFORDSHIRE, UK Colorectal cancer is the third most homeostasis. This structure allows colon cancer cells, leading to direct LANCE LIOTTA common neoplasm worldwide, but STs to bind to guanylyl cyclase C, influx of Ca2+. Depletion of extracel- NATIONAL CANCER INSTITUTE, epidemiologists have long been puz- which is specifically expressed by lular Ca2+ abolished the ability of STs BETHESDA, MD, USA zled by the fact that the incidence of intestinal epithelial cells. The interac- to inhibit cancer-cell proliferation, JANET D. ROWLEY this disease is lower in underdevel- tion activates the conversion of GTP whereas increasing Ca2+ levels restored UNIVERSITY OF CHICAGO MEDICAL CENTER, CHICAGO, oped countries. There is also an unex- to cyclic GMP (cGMP), activating a the antiproliferative effect of STs. IL, USA plained inverse correlation between downstream signalling pathway that This is the first study to show reg- colorectal cancer and enterotoxigenic results in secretory diarrhoea. ulation of cell proliferation by CNG DAVID SIDRANSKY JOHNS HOPKINS UNIVERSITY Escherichia coli infections. In fact, the Expression of guanylyl cyclase C, channels. Further research is SCHOOL OF MEDICINE, age-adjusted incidence of colorectal and also guanylin and uroguanylin, is required to determine the mecha- BALTIMORE, MD, USA cancer is lowest in underdeveloped frequently lost during cancer progres- nism by which the ST-induced Ca2+ JÜRG TSCHOPP countries in which enterotoxigenic sion, so this might be a tumour-sup- influx regulates DNA synthesis. The UNIVERSITY OF LAUSANNE, E. coli occurs at the highest rates. In pressive pathway. To support this authors indicate, however, that oral EPALINGES, SWITZERLAND Proceedings of the National Academy idea, inactivation of the mouse administration of agents that are BERT VOGELSTEIN of Sciences, Pitari et al. describe a guanylin gene results in increased involved in the intestinal salt and JOHNS HOPKINS ONCOLOGY mechanism by which these bacteria colonic proliferation. So how could water transport process might CENTER, BALTIMORE, MD, USA might prevent colon cancer. this pathway prevent cancer? prevent or treat colorectal cancer. ROBERT A. WEINBERG Enterotoxigenic E. coli produce Pitari et al. investigated the Kristine Novak WHITEHEAD INSTITUTE FOR heat-stable peptides (STs) that cause cGMP signalling pathway in human References and links BIOMEDICAL RESEARCH, the diarrhoea that is associated with colon cancer cells. They found that ORIGINAL RESEARCH PAPER Pitari, G. M. et al. CAMBRIDGE, MA, USA this bacterial infection. STs are likely addition of STs to cancer cells led to Bacterial endotoxins are associated with SAVIO WOO to cause this complication because increased intracellular cGMP con- resistance to colon cancer. Proc. Natl Acad. Sci. USA 10 Feb 2003 (doi: MOUNT SINAI SCHOOL OF they are structurally similar to the centrations, and also inhibited DNA 10.1073/pnas.0434905100) MEDICINE, NEW YORK, NY, USA endogenous peptides guanylin and synthesis and proliferation — but FURTHER READING Carrithers, S. L. Diarrhea of not in guanylyl-cyclase-C-null colorectal cancer: can bacterial toxins serve as a uroguanylin, which mediate control treatment for colon cancer? Proc. Natl Acad. Sci. of intestinal fluid and electrolyte tumour cells. So cGMP signalling USA 10 Feb 2003 [epub ahead of print]